Knockdown the moyamoya disease susceptibility gene, RNF213, upregulates the expression of basic fibroblast growth factor and matrix metalloproteinase-9 in bone marrow derived mesenchymal stem cells.

Moyamoya disease (MMD) is a chronic, progressive cerebrovascular occlusive disease. Ring finger protein 213 (RNF213) is a susceptibility gene of MMD. Previous studies have shown that the expression levels of angiogenic factors increase in MMD patients, but the relationship between the susceptibility gene RNF213 and these angiogenic mediators is still unclear. The aim of the present study was to investigate the pathogenesis of MMD by examining the effect of RNF213 gene knockdown on the expression of matrix metalloproteinase-9 (MMP-9) and basic fibroblast growth factor (bFGF) in rat bone marrow-derived mesenchymal stem cells (rBMSCs). Firstly, 40 patients with MMD and 40 age-matched normal individuals (as the control group) were enrolled in the present study to detect the levels of MMP-9 and bFGF in serum by ELISA. Secondly, Sprague-Dawley male rat BMSCs were isolated and cultured using the whole bone marrow adhesion method, and subsequent phenotypic analysis was performed by flow cytometry. Alizarin red and oil red O staining methods were used to identify osteogenic and adipogenic differentiation, respectively. Finally, third generation rBMSCs were transfected with lentivirus recombinant plasmid to knockout expression of the RNF213 gene. After successful transfection was confirmed by reverse transcription-quantitative PCR and fluorescence imaging, the expression levels of bFGF and MMP-9 mRNA in rBMSCs and the levels of bFGF and MMP-9 protein in the supernatant of the culture medium were detected on the 7th and 14th days after transfection. There was no significant difference in the relative expression level of bFGF among the three groups on the 7th day. For the relative expression level of MMP-9, there were significant differences on the 7th day and 14th day. In addition, there was no statistically significant difference in the expression of bFGF in the supernatant of the RNF213 shRNA group culture medium, while there was a significant difference in the expression level of MMP-9. The knockdown of the RNF213 gene affects the expression of bFGF and MMP-9. However, further studies are needed to determine how they participate in the pathogenesis of MMD. The findings of the present study provide a theoretical basis for clarifying the pathogenesis and clinical treatment of MMD.

Dysfunction of processing task-irrelevant emotional faces in primary insomnia patients: an evidence from expression-related visual MMN.

PURPOSE: According to the cognitive processing perspectives, patients with insomnia have insufficient neural management of expressional information. In this study, we compared the pre-attentive processing function of task-irrelevant facial expressions in patients with primary insomnia (PI) and matched healthy controls, with expression-related mismatch negativity (EMMN) elicited by emotional faces as the indicator. METHODS: Using three schematic facial expressions (neutral, happy, and sad) as task-irrelevant stimuli, we investigated the visual processing of PI patients (n = 22) and healthy subjects (n = 22) in an expression-related oddball paradigm designed to elicit the visual N170 and EMMN component. After recording and analyzing the electroencephalogram of all participants, amplitude analysis of N170 and EMMN was eventually conducted under corresponding time window. RESULTS: Compared with control group, the amplitude of sad-EMMN component was significantly attenuated in patients with PI, while no remarkable difference was observed under the happy condition. In addition, negative cognitive bias was further validated in the control group, but not presented in the PI group. CONCLUSION: The current data suggest dysfunctional expressional information processing in PI patients, accompanied by the disorganization of high level perceptual strategy of processing facial emotional expression.

Contingent negative variation for the periodicity of migraine attacks without aura.

Migraine is a primary neuropsychological disorder, although its etiology and pathogenesis are unknown. It has been reported that using contingent negative variation, the periodicity of migraine attacks is three days in adults. However, there is still a lack of relevant reports about the periodicity of migraine without aura in adults. Therefore, we investigated the changes of contingent negative variation in adults with migraine without aura from three to seven days after migraine attacks in order to provide the basis for exploring the circulation periodicity of migraine without aura. This prospective, observational study involved a group of 34 individuals with migraine without aura, who were screened during the three to seven days after a migraine attack without aura. A healthy group (31 individuals) was used as controls to assess the amplitudes of contingent negative variation and habituation of early contingent negative variation. Indices of the amplitudes included overall contingent negative variation, initial contingent negative variation, terminal contingent negative variation, and postoperative negative contingent variation. Differences between these indicators were analyzed. No significant difference was found between the patient and control groups for either the amplitudes of these measures of contingent negative variation or habituation of the early contingent negative variation for three to seven days after a migraine attack without aura (all P > 0.05). Thus, the study reported here found that the periodicity of migraine attacks without aura in adults is more than three days.

Female versus male migraine: an event-related potential study of visual neurocognitive processing.

BACKGROUND: Several studies have suggested cognitive deficits in migraineurs, and sex differences have also been observed in migraine, such as a higher prevalence in females. Nevertheless, little is known about gender-related differences in cognitive processing. In this study, we aimed to investigate the effect of gender on neurocognitive processing in migraineurs. METHODS: Altogether, 46 migraine patients without aura (23 females; mean age 32.848 years) during the interictal period and 46 age-matched healthy controls (23 females; mean age 32.652 years) were recruited. The emotional characteristics of participants were evaluated, and attentive processing was analyzed via event-related potential examinations using a three-stimulus visual oddball paradigm. RESULTS: We found that migraineurs suffered from emotional and visual cognitive processing abnormalities compared with healthy controls, including higher levels of anxiety and reduced P3 amplitude. These parameters were modulated by gender in migraine patients, but not in healthy participants. Our findings indicated that female patients seemed to be more anxious and have more severe impairment in attentive processing of visual stimuli than their male counterparts. The gender-related differences in migraineurs were further validated using event-related potential difference waveforms. CONCLUSIONS: These results suggested that migraine might have an additional influence on females and lead to more dysfunction in their interictal neurocognitive processing. Our findings provide evidence that a gender effect exists in migraineurs, which should be considered when designing experiments and exploring treatment approaches. The gender-related differences and underlying mechanisms deserve further investigation for patients with migraine.

Selective Impairment of Attentional Networks of Executive Control in Middle-Aged Subjects with Type 2 Diabetes Mellitus.

BACKGROUND The influence of type 2 diabetes mellitus (T2DM) on attention has been elusive. The Attention Network Test (ANT) was developed to evaluate the functioning of 3 individual attentional networks: orienting, alerting, and executive control. The purpose of this study was to use the ANT to assess attentional function and its sub-components in T2DM patients ages 40-60 years. MATERIAL AND METHODS Thirty T2DM patients and 30 healthy controls ages 40-60 years were recruited in this investigation. The ANT was used to statistically compare the efficiency among 3 sub-components of the attention networks between middle-aged T2DM patients (n=30) and gender-, age-, and education-matched healthy controls (n=30). RESULTS The ANT demonstrated a significant difference in executive control network between the T2DM patients and healthy controls (t=3.242, P=0.002), whereas no significant difference was observed regarding the domains of alerting (t=0.515, P=0.609) and orienting control (t=0.078, P=0.938) between the T2DM patient group and the healthy control group. Moreover, the mean reaction time in the ANT in the T2DM patients was significantly longer compared with that in the healthy controls (t=3.561, P=0.001). CONCLUSIONS The ANT reveals significant impairment in the executive control of middle-aged patients diagnosed with T2DM, whereas no significant impairment was observed in the domains of alerting and orienting.

Brain-targeted lycopene-loaded microemulsion modulates neuroinflammation, oxidative stress, apoptosis and synaptic plasticity in ß-amyloid-induced Alzheimer's disease mice.

OBJECTIVES: ß-Amyloid protein (Aß) plays pivotal roles in pathogenesis of Alzheimer's disease (AD) and triggers various pathophysiological events. Lycopene is a promising neuroprotector with multiple bioactivities, while its bioavailability is limited. Lycopene-loaded microemulsion (LME) possessing superior bioavailability and brain-targeting efficiency was developed in our previous study. In this investigation, we aimed to comprehensively evaluate its neuroprotective effects and underlying mechanisms using intracerebroventricular (ICV) Aß1-42 injection mice. METHODS: Mice were assigned to the Sham, Aß, Aß + LME and Aß + lycopene dissolved in olive oil (LOO) groups. ICV Aß1-42 administration was performed, followed by oral gavage of brain-targeted LME or conventional LOO formulation for 3 weeks. Brain samples were harvested for immunohistochemistry, biochemical assays and western blotting analyses. RESULTS: Our findings verified Aß-induced neurotoxicity on neuroinflammation, oxidative stress, apoptosis, Aß metabolisms and synaptic plasticity. LME supplementation dramatically attenuated astrocytosis and microgliosis, decreased malondialdehyde production and rescued antioxidant capacities, normalized apoptotic parameters and alleviated neuronal loss, inhibited amyloidogenic processing and activated non-amyloidogenic pathway, together with upregulating synaptic protein expressions and restoring synaptic plasticity. Nevertheless, most of these phenomena were not observed for mice treated with LOO, implying that LME showed significantly higher therapeutic efficacy against Aß injury. DISCUSSION: In summary, brain-targeted LME could exert neuroprotective function via suppressing a series of cascades triggered by Aß aggregates, thus ameliorating Aß neurotoxicity and associated abnormalities. Given this, LME may serve as an attractive candidate for AD prevention and treatment, and superiority of brain-targeting delivery is highlighted.

Insidious Attentional Deficits in Patients With Cerebral Small Vessel Disease Revealed by Attention Network Test.

Background: Several reports have indicated potential cognitive decline for cerebral small vessel disease (CSVD), especially in attention domain, whereas the attentional function at network level is still elusive. In this study, we used the attention network test (ANT) paradigm to characterize the efficiency of the alerting, orienting, and executive control networks in patients with CSVD and explore possible correlations between attention network efficiencies and obtained CSVD total score. Methods: A total of 31 patients with CSVD and 30 healthy controls matched for age, gender, and education level were recruited. After neuropsychological and anxiety/depression/somatization assessments, an original version of ANT containing different cue conditions and target stimuli was used to investigate independent attentional components, and then, behavioral performance (accuracy and reaction time) and network efficacy were recorded and analyzed. Results: Assessed by traditional neuropsychological scale (MoCA), we did not find difference between groups on general cognition. Nevertheless, the overall reaction time to targets of ANT was markedly prolonged in patients with CSVD, and similar phenomenon was observed for overall accuracy on ANT. Moreover, patients showed significantly lower orienting and executive control network efficiencies compared with controls, while not for alerting network. These impairments were correlated with total CSVD burdens, but not with anxiety, depression, or somatization. Conclusions: Although general and almost all individual cognitive function evaluated by MoCA seemed to remain intact, the orienting and executive control function was impaired in individuals with CSVD, which was modulated by lesion grades. Our observations implied insidious attentional deficits regarding CSVD. Given this, considering its simplicity and sensitivity, ANT could serve as an attractive tool for early diagnosis of cognitive dysfunction. Further investigations on the availability of ANT detection for CSVD are warranted.

Preliminary Findings on Visual Event-Related Potential P3 in Asymptomatic Patients with Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease is the primary cause of cognitive impairment. Therefore, early recognition is of great significance. Some studies have shown that asymptomatic cerebral small vessel disease (aCSVD) patients have abnormal neurocognitive function, but this is not readily apparent at the initial stage. The objective of this paper was to assess visual spatial attention by event-related potential (ERP) examination and to analyze the relationship between ERP data and clinical characteristics in patients with aCSVD. METHODS: We selected 25 aCSVD patients and enrolled 23 age-matched normal subjects as the control group. We measured the latency and amplitude of original/corresponding differential ERP components using the modified visual oddball paradigm, which included a standard stimulus, target stimulus, and new stimulus. Additionally, we selected aberrant ERP components to study the correlations between the ERP data and clinical characteristics of the patients with aCSVD. RESULTS: We found not only lower amplitude but also significantly longer P3 latency in the aCSVD patients. The above results were further verified by analyzing the different components (target minus standard and novel minus standard) of P3. Furthermore, abnormal ERPs in the aCSVD patients were closely related to the changes observed with imaging. CONCLUSION: It was demonstrated that the speed and capability of processing visual spatial information was impaired in aCSVD patients compared with healthy controls. Thus, ERP examination could detect the presence of attentional deficits and might become a rapid and sensitive method for the early diagnosis of aCSVD. However, its availability needs further investigation.

Selective Impairment of Processing Task-Irrelevant Emotional Faces in Cerebral Small Vessel Disease Patients.

BACKGROUND: Few reports have implied electrophysiological alterations and neurocognitive abnormalities in patients with cerebral small vessel disease (CSVD), while no investigation is available regarding emotional processing. In the present study, pre-attentive processing of facial expressions was compared between CSVD sufferers and healthy controls using expression-related visual mismatch negativity (EMMN) as the indicator. METHODS: A total of 22 CSVD patients (12 males) and 21 age-matched healthy controls (12 males) were recruited for neuropsychological and emotional assessments, as well as electroencephalogram recording and analysis. We employed an expression-related oddball paradigm to investigate automatic emotional processing, and a series of schematic emotional faces (neutral, happy, sad) unrelated to subject's task were present in the test to avoid low-level processing of facial features. RESULTS: Although the distinctions of neuropsychological (MoCA and MMSE), emotional (GAD-7 and PHQ-9) and behavioral parameters (reaction time to target stimuli and response accuracy) did not reach significant levels, mean amplitudes of sad EMMN in time intervals of 150-250 ms and 250-350 ms were remarkably reduced in CSVD patients compared with healthy controls, but not for happy EMMN. Furthermore, in the control group, sad EMMN was demonstrated to be larger (more negative) than happy EMMN, while this interesting phenomenon disappeared in the CSVD group. CONCLUSION: Our findings confirmed selective impairment of processing expressions which were task-irrelevant in CSVD patients, without the existence of negative bias (sad superiority) effect. The efficacy of EMMN as an electrophysiological evaluation marker of CSVD should be taken into account in future investigations.

Prevalence of mild cognitive impairment in type 2 diabetes mellitus is associated with serum galectin-3 level.

AIMS/INTRODUCTION: Galectin-3 (Gal3) contributes to insulin resistance, inflammation and obesity, the three risk factors for mild cognitive impairment (MCI) in type 2 diabetes mellitus patients. MATERIALS AND METHODS: A total of 134 hospitalized type 2 diabetes mellitus patients were assessed by the Montreal Cognitive Assessment method, and divided into 65 MCI and 69 controls. Levels of variables, Gal3 and Aß42, were investigated in relation with cognitive function in both type 2 diabetes mellitus patients with MCI and high-fat diet/streptozotocin induced type 2 diabetes mellitus rats. RESULTS: Significantly higher levels of serum Gal3 and lower levels of plasma Aß42 (all P < 0.05) were found in the MCI type 2 diabetes mellitus group as compared with the non-MCI type 2 diabetes mellitus control. Partial correlation analysis showed that Gal3 is negatively correlated with both MMSE score (r = -0.51, P < 0.01) and Montreal Cognitive Assessment score (r = -0.47, P < 0.001) after adjustment for glycated hemoglobin, homoeostasis model assessment of insulin resistance and Aß42 in all type 2 diabetes mellitus patients, with a stronger effect seen in the MCI type 2 diabetes mellitus group after further analysis with MCI strata. A simple logistic regression model showed that Gal3 and Aß42 are significantly associated with MCI type 2 diabetes mellitus patients after adjustment with the covariates sex, age, body mass index, glycated hemoglobin, homoeostasis model assessment of insulin resistance and antidiabetic drugs. Serum and brain Gal3 levels were significantly increased in high-fat diet/streptozotocin diabetic rats, which correlate to the impairment of learning and memory ability. Gal3 inhibitor modified citrus pectin decreased serum and brain Gal3 levels in diabetic rats, accompanied by the amelioration of learning and memory impairment. CONCLUSIONS: Gal3 might be associated with cognitive impairment in type 2 diabetes mellitus, and serum Gal3 level might be a new risk factor of MCI in type 2 diabetes mellitus patients.

Dysfunction in Automatic Processing of Emotional Facial Expressions in Patients with Obstructive Sleep Apnea Syndrome: An Event-Related Potential Study.

AIM: Obstructive sleep apnea syndrome (OSAS) is a prevalent chronic disease characterized by sleep fragmentation and intermittent hypoxemia. Several studies suggested that electrophysiological changes and neurocognitive abnormalities occurred in OSAS patients. In this study, we compared automatic processing of emotional facial expressions schematic in OSAS patients and matched healthy controls via assessing expression-related mismatch negativity (EMMN). METHODS: Twenty-two OSAS patients (mean age 44.59 years) and twenty-one healthy controls (mean age 42.71 years) were enrolled in this study. All participants underwent Montreal Cognitive Assessment (MoCA) scale test and polysomnographic recording. An expression-related oddball paradigm was used to elicit EMMN and the electroencephalogram was recorded and analyzed. Furthermore, Pearson's correlations were calculated to discuss the correlation between neuropsychological test scores, clinical variables and electrophysiological data. RESULTS: Compared with healthy controls, OSAS sufferers demonstrated significantly reduced EMMN mean amplitudes within corresponding time intervals, regardless of happy or sad conditions. Meanwhile, we observed that amplitude of sad EMMN was larger (more negative) than happy EMNN in healthy controls, while not in patients. Moderate correlations were found between MoCA test scores, sleep parameters and EMMN amplitudes. CONCLUSION: Our findings suggested pre-attentive dysfunction of processing emotional facial expressions in patients with OSAS, without the existence of negative bias effect. Moreover, correlation analysis showed that clinical characteristics of OSAS patients could affect EMMN amplitudes. Further studies on the advantages of EMMN as clinical and electrophysiological indicators of OSAS are warranted.

Pre-attentive dysfunction of processing emotional faces in interictal migraine revealed by expression-related visual mismatch negativity.

BACKGROUND: Several investigations have indicated emotional processing impairment in migraineurs, while no report is available considering the automatic processing of emotional information. In this study, we aimed to characterize the pre-attentive processing of facial expressions in migraine sufferers by recording and analyzing expression-related visual mismatch negativity (EMMN). METHODS: Altogether, 30 migraineurs (19 females) during the interictal period and 30 age-matched healthy controls (17 females) were recruited. An expression-related oddball paradigm was used to investigate automatic emotional processing, and a group of schematic emotional faces (neutral, happy, sad) unrelated to the participant's task were employed in the experiment in order to avoid low-level processing. RESULTS: There was no significant difference in behavioral performance (the response accuracy and reaction time) between migraine patients and healthy controls. Nevertheless, the mean EMMN amplitudes within the ranges of 150-250 ms and 250-350 ms were markedly attenuated in patients compared with controls, regardless of happy or sad condition (happy minus neutral or sad minus neutral), and sad EMMN was observed to be larger than happy EMMN only in healthy participants. Moreover, these electrophysiological data directly correlated with frequency and duration of migrainous attacks. CONCLUSIONS: Our findings implied that the pre-attentive dysfunction of processing both happy and sad expressions was demonstrated in interictal migraineurs, without the existence of negative bias (sad superiority) effect. Further studies on the availability of EMMN as an evaluative marker for migraine are warranted.

Selective attention network impairment during the interictal period of migraine without aura.

Attention deficits have been demonstrated in migraine patients during the interictal period, but these findings are not consistent across all studies. These inconsistencies may arise due to the different aspects of attention measured by various psychometric tests. Current theories divide attention into three separate domains subserved by separate networks: alerting, orienting, and executive control. The attention network test (ANT) was developed to measure all three attention networks and so may reveal more specific attention deficits among migraineurs. The aim of this study was to evaluate the attention function of migraine without aura (MwoA) patients using a series of neuropsychological scales and the ANT, and to assess the relationships between attention function and headache characteristics (e.g., history, frequency, and duration of each attack). Our results showed that MwoA patients exhibited significantly longer response times (RTs) of the executive control network, whereas no significant differences were observed in alerting and orienting network RTs between groups. MwoA patients also exhibited poorer performance than health control (HC) on the Stroop III and Shape Trail test B (STT B) tests. Spearman's analysis revealed positive correlations between executive control network RTs and both frequency and duration of migraine attack. MwoA patients demonstrate impairments of the executive control network, which appear to be exacerbated by more frequent and longer migraine attacks.